Quinolinecarboxylic acid derivative or its salt

ABSTRACT

The present invention relates a 1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid or salt thereof; and drugs containing the same as the active ingredient. Since this compound or salt thereof is highly stable to light while sustaining the excellent properties inherent to quinolone antibacterial agents, an antibacterial agent comprising, as an active ingredient, the invention compound or salt thereof can be stored over a long period of time without suffering from any decrease in the drug effect and can therefore be supplied as stable preparations such as injections, eye drops and surgical medicines.

TECHNICAL FIELD

The present invention relates to quinolinecarboxylic acid derivatives orsalts thereof having excellent antibacterial action and photostability,and antibacterial agents containing the same.

BACKGROUND ART

Since compounds having quinolinecarboxylic acid as a basic skeleton areexcellent in antimicrobial activity and broad antibacterial spectrum, anumber of useful ones as synthetic antibacterial agents are known. Amongthem, norfloxacin (Japanese Patent Application Laid-Open No. Sho53-141286), enoxacin (Japanese Patent Application Laid-Open No. Sho55-31042), ofloxacin (Japanese Patent Application Laid-Open No. Sho57-46986), ciprofloxacin (Japanese Patent Application Laid-Open No. Sho58-74667), tosufloxacin (Japanese Patent Application Laid-Open No. Sho60-228479) and the like have wide clinical utility as therapeutic agentsfor infectious diseases.

These compounds are, however, still insufficient in antimicrobialactivity, intestinal absorption and metabolic stability, and inaddition, they are known to cause cytotoxicity or photodermatosis. Thus,many problems remain unsolved.

It is reported that some quinolinecarboxylic acid compounds are notstable to light and happen to be colored or decomposed when exposed tolight. Consideration must be taken for some of their dosage forms so asto pharmaceutically overcome this drawback.

DISCLOSURE OF THE INVENTION

An object of the present invention is therefore to provide a compoundwhich has reduced side effects, is excellent in antimicrobial activity,intestinal absorption and metabolic stability and is optically stable.

Under such circumstances, the present inventors found thatpyridonecarboxylic acid derivatives each represented by the followingformula (I):

[wherein R¹ represents a hydrogen atom or a carboxyl protective group;R² represents a hydroxyl group, a lower alkoxy group, or a substitutedor unsubstituted amino group; R³ represents a hydrogen atom or a halogenatom; R⁴ represents a hydrogen atom or a halogen atom; R⁵ represents ahalogen atom or an optionally substituted saturated cyclic amino group;R⁶ represents a hydrogen atom, a halogen atom, a nitro group, or anoptionally protected amino group; X, Y and Z may be the same ordifferent and respectively represent a nitrogen atom, —CH═ or —CR⁷═(wherein R⁷ represents a lower alkyl group, a halogen atom, or a cyanogroup) (with the proviso that at least one of X, Y and Z represents thenitrogen atom), and W represents a nitrogen atom or —CR⁸═ (wherein R⁸represents a hydrogen atom, a halogen atom, or a lower alkyl group)], orsalts thereof have excellent antibacterial properties against both gramnegative and gram positive bacteria and have a markedly low toxicity sothat they are useful as a synthetic antibacterial agent, and alreadyfiled an international application (WO97/11068) for it.

The present inventors have proceeded with a further investigation onphotostability. As a result, it has been found that among theabove-described pyridonecarboxylic acid derivatives (I),1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound 1) of the following formula:

which has a 6-amino-3,5-difluoropyridinyl group on position 1, ahydroxyazetidinyl group on position 7 and a methyl group on position 8,or salt thereof has markedly high photostability so as to permitformulation into any dosage form as a preventive or remedy of variousinfectious diseases, while sustaining strong antimicrobial activity andlow toxicity inherent to the pyridonecarboxylic acid derivatives of theformula (I), leading to the completion of the invention.

In the present invention, there is thus provided1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid or salt thereof.

In the present invention, there is also provided a drug comprising saidcompound or salt thereof as an active ingredient.

In the present invention, there is also provided a pharmaceuticalcomposition comprising said compound or salt thereof and apharmaceutically acceptable carrier.

In the present invention, there is also provided the use of saidcompound or salt thereof for the preparation of a drug.

Furthermore, in the present invention, there is also provided a methodfor treating infectious diseases, characterized by administering saidcompound or salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a time-dependent change of UV spectrum after a solutioncontaining Compound 1 was exposed to UVA;

FIG. 2 shows a time-dependent change of UV spectrum after a solutioncontaining Comparative Compound 1 was exposed to UVA; and

FIG. 3 shows a time-dependent change of UV spectrum after a solutioncontaining Comparative Compound 2 was exposed to UVA.

BEST MODE FOR CARRYING OUT THE INVENTION

The compound according to the present invention has a6-amino-3,5-difluoropyridinyl group on position 1, a hydroxyazetidinylgroup on position 7 and a methyl group on position 8, each ofquinolinecarboxylic acid.

It is widely disclosed in WO97/11068 that quinolinecarboxylic acidshaving a 6-amino-3,5-difluoropyidinyl group on position 1 areantibacterial agents having excellent antibacterial action as well aslow toxicity. Among them, those having a hydroxyazetidinyl group onposition 7 are so-called acidic quinolone compounds. Since they exhibitefficacy against bacteria at the inflammatory site which tend to havereduced pH in a living body environment, bacteria englobed by amacrophage or neutrophil, intracellular parasitic bacteria and the like,they are presumed to be particularly useful when clinically applied. Theacidic quinolone compounds, which have so far been found, however showan undesirable tendency to be decomposed in a relatively short time inan aqueous solution by exposure to ultraviolet rays (FIGS. 2 and 3).

It is an utterly unexpected fact that the invention compound having amethyl group introduced on position 8 is hardly decomposed by exposureto light for long hours, thus exhibiting high photostability (FIG. 1)and at the same time, it has all the excellent properties whichcompounds of the similar series possess (Tests (1) and (2)).

The compounds of the present invention can each be converted into bothacid addition salts and base addition salts. Incidentally, these saltsinclude those formed into chelate salts with a boron compound.

Examples of the acid addition salt include (i) salts with a mineral acidsuch as hydrochloric acid or sulfuric acid, (ii) salts with an organiccarboxylic acid such as formic acid, citric acid, trichloroacetic acid,trifluoroacetic acid, fumaric acid or maleic acid, and (iii) salts witha sulfonic acid such as methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, mesitylenesulfonic acid or naphthalenesulfonicacid. Examples of the base addition salt include (i′) salts with analkali metal such as sodium or potassium, (ii′) salts with an alkalineearth metal such as calcium or magnesium, (iii′) ammonium salt, (iv)salts with a nitrogen-containing organic base such as trimethylamine,triethylamine, tributylamine, pyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine,procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine orN,N′-dibenzylethylenediamine. Examples of the boron compound includeboron halides such as boron fluoride and lower acyloxy borons such asacetoxy boron.

The compounds or salts thereof can exist not only in unsolvated formsbut also in hydrated or solvated forms. Accordingly, the compounds ofthe present invention embrace those in any crystalline form, andhydrated and solvated forms.

The compounds or salts thereof are prepared by any desired process. Thefollowing is one example of it.

[wherein, R¹ and R² each represents a lower alkyl group and R³represents a hydrogen atom or an amino protective group].

Invention compound 1 can be prepared by reacting Compound (A) with anorthoformate such as ethyl orthoformate or methyl orthoformate toproduce Acrylate derivative (B), reacting the acrylate derivative withAmino compound (C) into Compound (D), cyclizing the resulting compoundto produce compound (E), hydrolyzing the resulting compound intocompound (F) and then reacting the resulting compound with3-hydroxyazetidine.

Examples of the lower alkyl group represented by R¹ or R² include C₁₋₄alkyl groups such as methyl, ethyl, propyl and butyl. Examples of theamino protective group represented by R³ include t-butylamino, benzyl,p-methoxybenzyl and 1,1,3,3-tetramethylbutyl groups.

Compound (A) and an orthoformate are usually reacted at 0 to 160° C.,preferably at 50 to 150° C., and the reaction time usually ranges from10 minutes to 48 hours, preferably from 1 to 10 hours. The orthoformateis used in at least an equimolar amount, more preferably, in a molaramount about 1 to 10 times, both relative to Compound (A). As a reactionassistant, addition of a carboxylic anhydride such as acetic anhydrideis desired. The reaction assistant is added in an amount of at least anequimolar amount, more preferably, in a molar amount about 1 to 10times, both relative to Compound (A).

The reaction with Compound (C) is carried out in a proper solvent or ina solventless manner. Any solvent inert to the reaction can be used andexamples include aromatic hydrocarbons such as benzene, toluene andxylene, ethers such as diethyl ether, tetrahydrofuran, dioxane,monoglyme and diglyme, aliphatic hydrocarbons such as pentane, hexane,heptane and ligroin, halogenated hydrocarbons such as methylenechloride, chloroform and carbon tetrachloride, aprotic polar solventssuch as dimethylformamide and dimethylsulfoxide, and alcohols such asmethanol, ethanol and propanol. This reaction is usually carried out at0 to 150° C., preferably 0 to 100° C. and the reaction time usuallyranges from 10 minutes to 48 hours. Compound (C) is used in at least anequimolar amount, preferably in a molar amount 1 to 2 times, bothrelative to Compound (B).

Alternatively, Compound (D) can be obtained by reacting Compound (A)with an acetal such as N,N-dimethylformamide dimethylacetal orN,N-dimethylformamide diethylacetal and then reacting the reactionmixture with Compound (C). Any solvent inert to this reaction can beused for the reaction with an acetal. For example, the above-exemplifiedones can be employed. The reaction is usually effected at 0 to 150° C.,preferably at room temperature to 100° C. and the reaction time rangesfrom 10 minutes to 48 hours, preferably 1 to 10 hours.

The reaction to obtain Compound (E) by subjecting Compound (D) tocyclization is carried out in a proper solvent in the presence orabsence of a basic compound. Any solvent inert to the reaction can beused for this reaction. Examples include aromatic hydrocarbons such asbenzene, toluene and xylene, ethers such as diethyl ether,tetrahydrofuran, dioxane, monoglyme and diglyme, halogenatedhydrocarbons such as methylene chloride, chloroform and carbontetrachloride, dipolar aprotic solvents such as dimethylformamide anddimethylsulfoxide, and alcohols such as methanol, ethanol and propanol.Examples of the basic compound include alkali metals such as metalsodium and metal potassium, metal hydrides such as sodium hydride andcalcium hydride, inorganic salts such as sodium hydroxide, potassiumhydroxide, sodium carbonate and potassium carbonate, alkoxides such assodium methoxide, sodium ethoxide and potassium-t-butoxide, metalfluorides such as sodium fluoride and potassium fluoride, and organicbases such as trimethylamine, 1,8-diazabicyclo[5.4.0]undecene (DBU).

This reaction is usually effected at 0 to 200° C., preferably at roomtemperature to 180° C. and the reaction is usually completed in 5minutes to 24 hours. The basic compound is used in at least an equimolaramount, preferably in a molar amount 1 to 2 times, both relative toCompound (D).

Compound (F) can be obtained by hydrolyzing Compound (E), therebyeliminating the carboxy protective group of R¹ and/or amino protectivegroup of R³.

The hydrolysis can be carried out under any reaction condition used forusual hydrolysis. It is, for example, conducted in the presence of abasic compound such as sodium hydroxide, potassium hydroxide, sodiumcarbonate or potassium carbonate, a mineral acid such as hydrochloricacid, sulfuric acid or hydrobromic acid, or an organic acid such asp-toluenesulfonic acid, in a solvent, for example, water, an alcoholsuch as methanol, ethanol or propanol, an ether such as tetrahydrofuranor dioxane, a ketone such as acetone or methyl ethyl ketone, or aceticacid, or a mixed solvent thereof. This reaction is usually carried outat room temperature to 180° C., preferably at room temperature to 140°C. and the reaction time usually ranges from 1 to 24 hours.

Then, Compound (F) is reacted with 3-hydroxyazetidine or acid additionsalt thereof to obtain Invention compound 1.

This reaction is carried out in a solvent inert to the reaction, forexample, an aromatic hydrocarbon such as benzene, toluene or xylene, analcohol such as methanol or ethanol, an ether such as tetrahydrofuran,dioxane or monoglyme, a halogenated hydrocarbon such as methylenechloride, chloroform or carbon tetrachloride, a aprotic polar solventsuch as dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone,acetonitrile or pyridine, optionally in the presence of a deacidifyingagent such as sodium carbonate, calcium carbonate, triethylamine or1,8-diazabicyclo[5.4.0]undecene (DBU) at room temperature to 160° C. Thereaction time ranges from several minutes to 48 hours, preferably 10minutes to 24 hours. 3-Hydroxyazetidine is preferably added in at leastan equimolar amount, more preferably, in a molar amount 1 to 5 times,both relative to Compound (F).

Compound 1 can be converted into a corresponding acid addition salt orbase addition salt in a conventional manner, for example, by the methoddescribed below.

Specifically, the conversion is carried out by treating Inventioncompound 1 at room temperature or under heat as desired in the presenceof a mineral acid such as hydrochloric acid or sulfuric acid, an organiccarboxylic acid such as formic acid, citric acid, trichloroacetic acid,trifluoroacetic acid, fumaric acid or maleic acid, a sulfonic acid suchas methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,mesitylenesulfonic acid or naphthalenesulfonic acid, a basic compoundsuch as sodium hydroxide, potassium hydroxide, calcium hydroxide ormagnesium hydroxide or a nitrogen-containing organic base such asammonium, trimethylamine, triethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,diethylamine, cyclohexylamine, procaine, dibenzylamine,N-benzyl-β-phenethylamine, 1-efenamine or N,N′-dibenzylethylenediaminein a polar solvent, for example, an alcohol such as methanol or ethanolor water.

Incidentally, the starting compound (A) can be prepared by any one ofthe processes described in the below-described documents or by a similarprocess.

(1) J. Heterocyclic Chem. 22, 1033(1985)

(2) Liebigs Ann. Chem. 29(1987)

(3) J. Med. Chem. 31, 991(1988)

(4) J. Org. Chem. 35, 930(1970)

(5) Japanese Patent Application Laid-Open No. Sho 62-246541

(6) Japanese Patent Application Laid-Open No. Sho 62-26272

(7) Japanese Patent Application Laid-Open No. Sho 63-145268

(8) J. Med. Chem. 29, 2363(1986)

(9) J. Fluorin. Chem. 28, 361(1985)

(10) Japanese Patent Application Laid-Open No. Sho 63-198664

(11) Japanese Patent Application Laid-Open No. Sho 63-264461

(12) Japanese Patent Application Laid-Open No. Sho 63-104974

(13) European Patent Application No. 230948

(14) Japanese Patent Application Laid-Open No. Hei 2-282384

(15) Japanese Language Laid-Open Publication (PCT) No. Hei 3-502452

(16) J. Heterocyclic Chem. 27, 1609(1990)

(17) Japanese Patent Application Laid-Open No. Hei 7-215913

(18) WO97/40036

The starting compound (C) can be prepared in any desired process. It maybe prepared, for example, by a substituting the halogen atom, which hasbeen bonded to the carbon atom constituting the 6-membered ring, with anamine derivative, for example, in accordance with a known halogen-aminesubstitution reaction as described in WO97/11068 or WO97/38971.

The invention compound thus obtained can be isolated and purified in aconventional manner and it is available in the form of a salt or a freecarboxylic acid, depending on the isolation and purification conditions.The form of the compound, however, may be converted into another form,and thus, the compound of the present invention can be prepared in adesired form.

Although the compound or salt thereof thus obtained is an acidicquinolone compound, it has excellent photostability so as tosubstantially prevent decomposition even by exposure to light for longhours, while sustaining excellent antibacterial activity and excellentproperties free from side effects such as phototoxicity which areinherent to pyridonecarboxylic acid derivatives represented by theformula (I).

The compound or salt thereof according to the present invention may beformulated into an antibacterial composition with a pharmaceuticallyacceptable carrier for parenteral administration such as injection,rectal administration or ophthalmic administration, or oraladministration in the solid or liquid form.

Preparations of the present invention for use as injections can take theform of pharmaceutically acceptable germ-free aqueous solutions,nonaqueous solutions, suspensions or emulsions. Examples of the suitablenon-aqueous carrier, diluent, solvent or vehicle include propyleneglycol, polyethylene glycol, vegetable oils such as olive oil andinjectable organic esters such as ethyl oleate. In such a solution, anadjuvant such as antiseptic, humectant, emulsifier or dispersant can beincorporated as needed. These injections can be sterilized, for example,by filtering them through a bacterial filter or by mixing, immediatelybefore use, a sterilizing agent or a sterilizing agent in the form of agerm-free solid composition soluble in some other sterilizable andinjectable media.

Preparations for ophthalmic administration may each preferably contain,in addition to the invention compound, a solubilizing agent,preservative, isotonic agent, thicker and the like as needed.

Examples of the orally administrable solid preparation include capsules,tablets, pills, powders and granules. Upon formulation of such a solidpreparation, the compound according to the present invention is mixedwith at least one inert diluent such as sucrose, lactose or starch. Uponusual formulation, one or more substances other than the inert diluent,for example, a lubricant (e.g., magnesium stearate) can also beincorporated in the preparation. A buffer can also be incorporated incapsules, tablets or pills, whereas enteric coating may be applied totablets or pills.

Examples of the orally administrable liquid preparation includeordinarily employed inert diluents such as, in addition to water,pharmaceutically acceptable emulsions, solutions, suspending agents,syrups and elixirs. In addition to such an inert diluent, adjuvants suchas sweetening agent, seasoning agent and flavor as well as humectant,emulsifier and suspending agent may be incorporated.

The transrectally administrable preparations may contain, in addition tothe invention compound, an excipient such as cacao butter or suppositorywax as needed.

Although the dosage of the invention compound varies depending on theproperties of the compound, administration route, desired treatment termand other factors, the compound is generally administered in an amountof about 0.1 to 1000 mg/kg a day, with about 0.5 to 100 mg/kg beingparticularly preferred. If desired, this daily dosage may beadministered in 2 to 4 portions.

EXAMPLES

present invention will hereinafter be described more specifically by thefollowing examples and referential examples.

Referential Example 1 Synthesis of ethyl1-(6-t-butylamino-3,5-difluoropyridin-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate

To 3.4 g of ethyl 2,4,5-trifluoro-3-methylbenzoylacetate were added 3.2g of acetic anhydride and 2.3 g of triethyl orthoformate, followed byheating under reflux for 4 hours. After removal of the solvent bydistillation, toluene was added to the residue for azeotropicdistillation. To the residue was added 5 ml of ethanol. At 0° C., asolution of 2.7 g of 2-amino-6-t-butylamino-3,5-difluoropyridinedissolved in 20 ml of ethanol was added dropwise, followed by stirringat room temperature for 20 minutes. The reaction mixture was distilledto remove the solvent and the residue was subjected to chromatography ona silica gel column. From the eluate fraction of ethylacetate-hexane=1:8, 4.6 g of ethyl2-(2,4,5-trifluoro-3-methylbenzoyl)-3-(6-t-butylamino-3,5-difluoropyridin-2-yl)aminoacrylatewas obtained as an oil. To a solution of 4.6 g of the resulting ethyl2-(2,4,5-trifluoro-3-methylbenzoyl)-3-(6-(t-butylamino-3,5-difluoropyridin-2-yl)aminoacrylatein 10 mL of N,N-dimethylformamide, was added 1.4 g of potassiumcarbonate, followed by stirring at 100° C. for 50 minutes. Water andethyl acetate were added to the reaction mixture for extraction. Theorganic layer was then separated from the extract, dried over magnesiumsulfate and distilled to remove the solvent. The residue was collectedby filtration using ethanol and then washed with diethyl ether, whereby2.6 g of the title compound was obtained as a pale yellow powder.

Melting point: 207 to 211° C.

¹HNMR (d₆-DMSO) δ; 1.34-1.48(m,12H), 1.82(d,J=3 Hz,3H), 4.40(q,J=7Hz,2H), 4.75(brs,1H), 7.23(t, J=9 Hz,1H), 8.22(t,J=10 Hz,1H),8.50(s,1H).

Referential Example 2 Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

To 2.5 g of ethyl1-(6-t-butylamino-3,5-difluoropyridin-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylatewas added 10 mL of 36% hydrochloric acid, followed by heating underreflux overnight. After the reaction mixture was allowed to cool down,the resulting precipitate was collected by filtration. The precipitatewas washed with ethanol and then with diethyl ether, whereby 1.7 g ofthe title compound was obtained as a pale yellow powder.

Melting point: 274 to 277° C.

¹HNMR (d₆-DMSO) δ; 1.84(s,3H), 6.91(brs,2H), 8.03(t,J=9 Hz,1H),8.25(t,J=9 Hz,1H), 8.93(s,1H).

Example 1 Synthesis of1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

To 5 mL of dimethylsulfoxide were added 1.8 g of1-(6-amino-3,5-difluoropyridin-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, 1.1 g of 3-hydroxyazetidine.hydrochloride, 0.6 g of lithiumhydroxide and 0.2 g of magnesium chloride, followed by stirring at roomtemperature for 21 hours. The reaction mixture was added to 60 mL of a10% aqueous solution of citric acid while stirring. The precipitate wascollected by filtration and then washed with water. The solid thusobtained was dispersed in 20 mL of ethanol, followed by heating underreflux for 15 minutes. The pale yellow precipitate was collected byfiltration and washed with ethanol. The solid thus obtained wasdissolved in 10 mL of pyridine and the resulting solution wasconcentrated under reduced pressure. The precipitate was collected byfiltration and washed with ethanol, whereby 1.3 g of the title compoundin the form of a pyridine complex was obtained as a pale yellow powder(melting point: 244 to 247° C.).

The resulting pyridine complex was dispersed in 50 mL of distilledwater, followed by heating under reflux for 20 minutes. The precipitatewas collected by filtration, washed with distilled water and dried overphosphorus pentaoxide under reduced pressure, whereby 1.1 g of the titlecompound was obtained.

Melting point: 245 to 247° C.

¹HNMR (d₆-DMSO) δ; 1.64(s,3H), 3.94(m,1H), 4.03(m,1H), 4.49(m,3H),5.69(d,J=5 Hz,1H), 6.85(brs,2H), 7.77(d,J=14 Hz,1H), 7.96(t,J=10 Hz,1H),8.72(s,1H)

Tests

The compounds according to the present invention were tested for theirantibacterial action, phototoxicity and photostability. The results willbe described below in (1) to (3). For comparison, used were1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.3-hydroxyazetidine salt (Comparative compound 1),1-(6-amino-3,5-difluoropyridin-2-yl)-6,8-difluoro-7-(3-hydroxyzetidin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Comparative compound 2) and commercially available1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (ciprofloxacin),S-(−)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylicacid (levofloxacin),(±)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (tosufloxacin) and 7-([1α, 5α,6α]-6-amino-3-azabicyclo[3.1.0]hex-1-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid (trovafloxacin).

(1) Test on Antibacterial Action

In accordance with the standard method established by Japan Society ofChemotherapy (CHEMOTHERAPY, 29(1),76(1981)), the minimum growthinhibitory concentration (MIC: μg/mL) was measured. The results areshown in Table 1.

TABLE 1 Compound Comparative Comparative 1 compound 1 compound 2Ciprofloxacin Levofloxacin S. aureus 209P 0.006 0.006 0.013 0.20 0.20 S.aureus Smith <0.003 0.003 0.006 0.20 0.10 MRSA W200 0.013 0.006 0.0250.78 0.39 S. epidermidis IFO12293 0.013 0.013 0.050 0.78 0.39 B.subtilis ATCC6633 0.025 0.05 0.025 0.05 0.10 E. coli NIHJ-JC2 0.05 0.050.10 0.013 0.05 K. peumoniae KC-1 0.05 0.05 0.10 0.025 0.05 P.aeruginosa IFO3445 0.39 0.39 0.39 0.39 0.78

(2) Test on Phototoxicity

The phototoxicity was tested in accordance with the following method.

After intravenous administration (40 mg/kg/10 mL) of each of the testcompounds to a female ICR mouse (5-6 week old), the mouse was exposed toultraviolet rays (320 to 400 nm, 1.8 mW/cm²/sec) for 4 hours. Its earswere observed for any abnormality after an elapse of each of 24 and 48hours, with the time rightly after exposure being designated as 0 hour,and evaluated based on the below-described criteria. The average scorewas calculated and results are shown in Table 2.

no abnormality (0 point); slight erythema (1 point); medium erythema (2points); and heavy erythema or edema (3 points)

TABLE 2 Scores (frequency) 0 hour 24 hours 48 hours Compound 1 0 (0/4) 0(0/4) 0 (0/4) Comparative compound 1 0 (0/4) 0 (0/4) 0 (0/4) Comparativecompound 2 0 (0/4) 0 (0/4) 0 (0/4) Tosufloxacin 1.8 (4/5) 0.8 (4/5) 0.2(1/5) Trovafloxacin 1.5 (4/4) 0 (0/4) 0 (0/4)

(2) Test on Photostability

The test on photostability was made in accordance with the followingmethod.

With 0.08% NaOH, 1 mg/mL of the test compound was prepared. Theresulting solution was diluted 100-fold with PBS(−). Into the wells of a24-well plate, 1.5 ml portions of the diluted solution were poured,respectively. Just after the solution was exposed to UVA under an UVlight (black light, product of Toshiba Corporation) for 0, 2, 5, 10 and20 minutes, UV spectra within a range of 190 to 400 nm were measured(“UV-240”, product of Shimadzu Corporation). The results are shown inFIGS. 1 to 3.

The above-described results demonstrate that the invention compound washardly decomposed by exposure to ultraviolet rays for 20 minutes.

Formulation Example 1 (Tablets)

To Compound 1 were added lactose, corn starch, crystalline cellulose,carmellose calcium and magnesium stearate in accordance with theformulation amounts as shown in Table 3, respectively, followed bymixing for 15 minutes in a Bohle container mixer (manufactured byKotobuki Engineering & Manufacturing Corp. Ltd.). The resulting powderswere compression-molded by a tableting machine (“CORRECT 19K”,manufactured by Kikusui Seisakusho, Ltd.), whereby tablets having adiameter of 8 mm and weight of 250 mg were obtained. The resultingtablets were found to have excellent hardness and intragastricdesintegration.

TABLE 3 weight Component % Compound 1  40 Lactose  24 Corn starch  17Crystalline cellulose  12 Carmellose calcium  6 Magnesium stearate  1Total 100

Formulation Example 2 (Injection)

To Compound 1 were added 2 g of glycerin (solubilizing assistant),polysorbate 80 (solubilizing agent) and distilled water for injection todissolve the former in the latter. To the resulting solution were addeda buffer and sodium chloride (isotonic agent), whereby 300 mL of anisotonic solution having pH 6.0 was obtained. The resulting solution wasfiltered through a membrane filter of 0.22 μm. A sterilized vial wasfilled with 30 ml of the filtrate, whereby an injection was prepared.

Formulation Example 3 (Ointment)

To 90 g of a hydrophilic plastibase was added 1 g of Compound 1,followed by uniform dispersion. To the resulting dispersion were added 3g of light silicic anhydride and 6 g of octadodecyl myristate and theresulting mixture was kneaded for 20 minutes. An aluminum tube wasfilled with 10 g of the kneaded mass, whereby an ointment containing 1%of Compound 1 was obtained.

Formulation Example 4 (Eye Drop)

In 100 mL of sterilized and purified water was dissolved 0.3 g ofCompound 1, followed by the addition of a buffer and sodium chloride,whereby an isotonic solution of pH 7.5 was obtained. A sterilizedcontainer was filled with 5 mL of the resulting solution, whereby an eyedrop containing 0.3% of Compound 1 was obtained.

INDUSTRIAL APPLICABILITY

The compounds or salts thereof according to the present inventionexhibit markedly stable light stability, while maintaining excellentantibacterial activity and excellent phototoxicity-free properties whichare inherent to quinolone-base antibacterial agents. Antibacterialagents comprising, as an active ingredient, the invention compound orsalt thereof can be stored over a long period of time without sufferingfrom any decrease in the drug effect, can be supplied as stablepreparations even in the dosage form of an injection, eye drop orsurgical medicine without any pharmaceutical device against exposure tolight and can be used widely not only as pharmaceuticals for humanbeings and animals but also as medicines for fishes, agriculturalchemicals or food preservatives.

What is claimed is:
 1. A1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid or a salt thereof.
 2. A pharmaceutical composition comprising a1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid or a salt thereof, and a pharmaceutically acceptable carrier.
 3. Apharmaceutical composition of claim 2, which is an antibacterialcomposition.
 4. A method for treating infectious diseases, whichcomprises administering to an individual in need thereof a1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid or a salt thereof.
 5. The pharmaceutical composition of claim 2,Which is a solid composition.
 6. The pharmaceutical composition of claim2, which is a liquid composition.
 7. The method of claim 4, wherein thecompound is administered parenterally.
 8. The method of claim 4, whereinthe compound is administered orally.
 9. The method of claim 4, whereinthe compound is administered in an amount of 0.1 to 1000 mg/kg per day.10. The method of claim 4, wherein the compound is administered in anamount of 0.5 to 100 mg/kg per day.
 11. A method of treating a bacterialinfection in an individual, comprising administering the compound ofclaim 1 to the individual in an amount to treat the bacterial infection.12. The method of claim 11, wherein the compound is administeredparenterally.
 13. The method of claim 11, wherein the compound isadministered orally.
 14. The method of claim 11, wherein the compound isadministered in an amount of 0.1 to 1000 mg/kg per day.
 15. The methodof claim 11, wherein the compound is administered in an amount of 0.5 to100 mg/kg per day.